To determine the effects of single nucleotide polymorphisms (SNPs) identified in a genome-wide association study of progressive supranuclear palsy (PSP), we tested their association with brain gene expression, CpG methylation and neuropathology. In 175 autopsied PSP subjects, we performed associations between seven PSP risk variants and temporal cortex levels of 20 genes in-cis, within ±100 kb. Methylation measures were collected using reduced representation bisulfite sequencing in 43 PSP brains. To determine whether SNP/expression associations are due to epigenetic modifications, CpG methylation levels of associated genes were tested against relevant variants. Quantitative neuropathology endophenotypes were tested for SNP associations in 422 PSP subjects. Brain levels of LRRC37A4 and ARL17B were associated with rs8070723; MOBP with rs1768208 and both ARL17A and ARL17B with rs242557. Expression associations for LRRC37A4 and MOBP were available in an additional 100 PSP subjects. Meta-analysis revealed highly significant associations for PSP risk alleles of rs8070723 and rs1768208 with higher LRRC37A4 and MOBP brain levels, respectively. Methylation levels of one CpG in the 3' region of ARL17B associated with rs242557 and rs8070723. Additionally, methylation levels of an intronic ARL17A CpG associated with rs242557 and that of an intronic MOBP CpG with rs1768208. MAPT and MOBP region risk alleles also associated with higher levels of neuropathology. Strongest associations were observed for rs242557/coiled bodies and tufted astrocytes; and for rs1768208/coiled bodies and tau threads. These findings suggest that PSP variants at MAPT and MOBP loci may confer PSP risk via influencing gene expression and tau neuropathology. MOBP, LRRC37A4, ARL17A and ARL17B warrant further assessment as candidate PSP risk genes. Our findings have implications for the mechanism of action of variants at some of the top PSP risk loci.

中文翻译：

---

进行性核上性麻痹风险基因座的基因表达，甲基化和神经病理学相关性。

为了确定在进行性核上性麻痹（PSP）的全基因组关联研究中确定的单核苷酸多态性（SNP）的影响，我们测试了它们与脑基因表达，CpG甲基化和神经病理学的关联。在175名经过尸检的PSP受试者中，我们进行了七个PSP风险变异与20个基因顺时针在±100 kb内的颞皮质水平之间的关联。在43个PSP大脑中使用减少的代表性亚硫酸氢盐测序来收集甲基化指标。为了确定SNP /表达关联是否是由于表观遗传修饰引起的，针对相关变体测试了相关基因的CpG甲基化水平。在422个PSP受试者中测试了定量神经病理学内表型的SNP关联。LRRC37A4和ARL17B的脑水平与rs8070723相关。具有rs1768208的MOBP以及具有rs242557的ARL17A和ARL17B。LRRC37A4和MOBP的表达关联在另外100个PSP受试者中可用。荟萃分析显示，rs8070723和rs1768208的PSP风险等位基因分别与较高的LRRC37A4和MOBP脑水平高度相关。与rs242557和rs8070723相关的ARL17B 3'区域中一个CpG的甲基化水平。此外，与rs242557相关的内含子ARL17A CpG和与rs1768208相关的内含MOBP CpG的甲基化水平。MAPT和MOBP区域的风险等位基因也与较高水平的神经病理学有关。rs242557 /螺旋体和簇状星形胶质细胞之间的关联最强。和用于rs1768208 /盘绕体和tau螺纹。这些发现表明，MAPT和MOBP基因座上的PSP变异体可能通过影响基因表达和tau神经病理而赋予PSP风险。MOBP，LRRC37A4，ARL17A和ARL17B作为候选PSP风险基因有待进一步评估。我们的发现对某些PSP最高风险基因座的变异体的作用机制有影响。